LONG-CIRCULATING LIPOSOMAL CAMPTOTHECINS

在这项赠款申请中，我们提出了令人振奋的新数据，表明喜树碱的长循环脂质体配方显著改善了血液稳定性，增强了药物循环半衰期，并显著增强了抗肿瘤活性。我们还介绍了我们最新的合成努力，开发了高效的A，B，E环修饰喜树碱，显示出显著改善人类血液稳定性的效果。我们现在打算将合理的药物设计与脂质体给药方法相结合，以产生长循环和肿瘤靶向的喜树碱脂质体制剂，用于癌症的治疗。我们的具体目标包括：1)开发新的和有效的7-烷氨基-高喜树碱以及7-硅烷基氨基高喜树碱拓扑异构酶I抑制剂，能够远程加载到隐形的长循环脂质体中；2)配制长循环的喜树碱脂质体(由于制造原因，它是制药行业非常喜欢的)，并利用我们的合成能力来创造喜树碱制剂，从而优化对肿瘤的药物输送；3)表征新类似物及其脂质体制剂的细胞药理和血液化学；4)在体内确定各种喜树碱脂质体对人体移植瘤的抗肿瘤活性和肿瘤定位；5)利用荧光成像技术，对裸鼠体内喜树碱脂质体在肿瘤部位的蓄积进行无创性原位研究。

Within this grant application we present exciting new data that demonstrate long-circulating liposomal formulations of camptothecins markedly improve blood stabilities, enhance drug circulation half-lives, and dramatically potentiate and enhance anti-tumor activities. We also describe our very recent synthetic efforts which have developed highly potent A,B,E-ring modified camptothecins displaying markedly improved human blood stabilities. We now intend to combine the rational drug design with liposomal delivery approaches to generate long-circulating and tumor- targeted liposomal camptothecin formulations for the treatment of cancer. Our specific aims include: 1) to develop novel and potent 7-alkylamino- homocamptotechin as well as 7-silylalkylaminohomocamptothecin topoisomerase I inhibitors capable of being remote-loaded into stealth-like, long-circulating liposomes; 2) to formulate long-circulating and is highly preferred by the pharmaceutical industry for manufacturing reasons) and to implement our synthetic abilities to create the camptothecin agents that display optimal retention in liposomes thereby optimizing drug delivery to the tumor; 3) to characterize the cellular pharmacology and blood chemistry of the new analogues and their liposomal formulations; 4) to determine in vivo anti-tumor activities, and tumor localization of the various camptothecin liposomal formulations against human xenografts; 5) to utilize fluorescence imaging methods to non-invasively study in situ the accumulation camptothecins delivered in liposomes at tumor sites in athymic nude mice.